KR970706849A - New tumor suppressor gene HIC-1 (NOVEL TUMOR SUPPRESSOR GENE.HIC-1) - Google Patents

New tumor suppressor gene HIC-1 (NOVEL TUMOR SUPPRESSOR GENE.HIC-1) Download PDF

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KR970706849A
KR970706849A KR1019970703250A KR19970703250A KR970706849A KR 970706849 A KR970706849 A KR 970706849A KR 1019970703250 A KR1019970703250 A KR 1019970703250A KR 19970703250 A KR19970703250 A KR 19970703250A KR 970706849 A KR970706849 A KR 970706849A
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비. 베일린 스티븐
마코스 웨일즈 미셸
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하워드 더블유. 칼리파노
더 존스 홉킨스 유니버시티 스쿨 오브 메디신
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Abstract

본발명은 신규의 종양 억제인자 HIC-1을 암호화하는 폴리뉴클레오티드 및 폴리펩티드 서열을 제공한다. 본 발명은 또한 HIC-1과 관련된 세포 증식성 질환의 검출 방법을 제공한다. HIC-1은 그러한 질환의 경과중에, 진단적, 예후적 및 치료적으로 사용될 수 있는 마커이다.The present invention provides polynucleotide and polypeptide sequences encoding novel tumor suppressor HIC-1. The invention also provides a method of detecting cell proliferative diseases associated with HIC-1. HIC-1 is a marker that can be used diagnostically, prognostically and therapeutically during the course of such a disease.

Description

신규의 종양 억제 유전자 에이치아이씨(HIC)-1(NOVEL TUMOR SUPPRESSOR GENE. HIC-1)New tumor suppressor gene HIC-1 (NOVEL TUMOR SUPPRESSOR GENE.HIC-1)

본 내용은 요부공개 건이므로 전문내용을 수록하지 않았음As this is a public information case, the full text was not included.

Claims (48)

주로 서열번호 3의 아미노산 서열로 구성되는 실질적으로 순수한 HIC-1(암에서 과메틸화된) 폴리펩티드.A substantially pure HIC-1 (hymethylated in cancer) polypeptide consisting predominantly of the amino acid sequence of SEQ ID NO. 서열번호 3의 아미노산 서열을 가진 폴리펩티드를 암호화하는 폴리뉴클레오티드 서열로 주로 구성되는 분리된 폴리뉴클레오티드 서열.An isolated polynucleotide sequence consisting mainly of a polynucleotide sequence encoding a polypeptide having an amino acid sequence of SEQ ID NO. 제2항에 있어서, 서열번호 3의 아미노산 서열을 가진 폴리펩티드를 암호화하는 폴리뉴클레오티드 서열로 주로 구성되고, HIC-1 폴리펩티드와 면역반응성이 있는 항체에 대한 하나 이상의 에피토프를 가지는 분리된 폴리뉴클레오티드 서열.3. The isolated polynucleotide sequence of claim 2, consisting mainly of a polynucleotide sequence encoding a polypeptide having the amino acid sequence of SEQ ID NO: 3, having one or more epitopes for an antibody that is immunoreactive with the HIC-1 polypeptide. 제2항에 있어서, 뉴클레오티드 서열이 a) T가 U일수도 있는 서열번호 1의 서열; b) 서열 a)와 상보적인 핵산 서열; c) 15개 이상의 염기 길이를 가지고, HIC-1을 암호화하는 게놈 DNA에 선택적으로 혼성화하는 상기 a) 또는 b) 서열의 단편으로 구성된 군에서 선택되는 폴리뉴클레오티드.The method of claim 2, wherein the nucleotide sequence is a) the sequence of SEQ ID NO: 1 wherein T may be U; b) a nucleic acid sequence complementary to sequence a); c) a polynucleotide having a length of at least 15 bases and selected from the group consisting of fragments of said a) or b) sequences that selectively hybridize to genomic DNA encoding HIC-1. 제2항의 폴리뉴클레오티드를 포함하는 재조합 발현 벡터.Recombinant expression vector comprising the polynucleotide of claim 2. 제5항의 발현 벡터를 포함하는 숙주 세포.A host cell comprising the expression vector of claim 5. 서열번호 3의 폴리펩티드에 결합하며, 서열번호 3의 면역반응성 단편과 결합하는 항체.An antibody that binds to a polypeptide of SEQ ID NO: 3 and binds to an immunoreactive fragment of SEQ ID NO: 3. 제7항에 있어서, 상기 항체가 다클론인 항체.8. The antibody of claim 7, wherein said antibody is polyclonal. 제7항에 있어서, 상기 항체가 단일클론인 항체.8. The antibody of claim 7, wherein said antibody is a monoclonal. HIC-1을 포함하는 표적 세포 성분을 HIC-1과 반응하는 시약과 접촉시키는 단계 및 HIC-1을 검출하는 단계를 포함하는, 피험자에서 HIC-1과 관련된 세포 증식성 질환을 검출하는 방법.A method for detecting a cell proliferative disease associated with HIC-1 in a subject, comprising contacting a target cell component comprising HIC-1 with a reagent that reacts with HIC-1 and detecting HIC-1. 제10항에 있어서, 상기 표적 세포 성분이 핵산인 방법.The method of claim 10, wherein said target cell component is a nucleic acid. 제11항에 있어서, 핵산이 DNA인 방법.The method of claim 11, wherein the nucleic acid is DNA. 제11항에 있어서, 핵산이 RNA인 방법.The method of claim 11, wherein the nucleic acid is RNA. 제11항에 있어서, 핵산이 과메틸화된 것인 방법.The method of claim 11, wherein the nucleic acid is hypermethylated. 제10항에 있어서, 상기 표적 세포 성분이 단백질인 방법.The method of claim 10, wherein said target cell component is a protein. 제10항에 있어서, 상기 시약이 프로브인 방법.The method of claim 10, wherein said reagent is a probe. 제16항에 있어서, 상기 프로브가 핵산인 방법.The method of claim 16, wherein said probe is a nucleic acid. 제16항에 있어서, 상기 프로브가 항체인 방법.The method of claim 16, wherein said probe is an antibody. 제18항에 있어서, 상기 항체가 다클론인 항체.The antibody of claim 18, wherein said antibody is polyclonal. 제18항에 있어서, 상기 항체가 단일클론인 항체.The antibody of claim 18, wherein said antibody is a monoclonal. 제16항에 있어서, 상기 프로브가 검출가능하게 표지된 것인 방법.The method of claim 16, wherein the probe is detectably labeled. 제21항에 있어서, 상기 표지가 방사성 동위원소, 생물발광성 화합물, 화학 발광성 화합물, 형광성 화합물, 금속 킬레이트 또는 효소로 구성된 군에서 선택되는 방법.The method of claim 21, wherein the label is selected from the group consisting of radioisotopes, bioluminescent compounds, chemiluminescent compounds, fluorescent compounds, metal chelates, or enzymes. 제10항에 있어서, 상기 시약이 제한 엔도뉴클레아제인 방법.The method of claim 10, wherein said reagent is a restriction endonuclease. 제23항에 있어서, 상기 제한 엔도뉴클레아제가 메틸화에 민감성인 방법.The method of claim 23, wherein said restriction endonuclease is sensitive to methylation. 제24항에 있어서, 상기 제한 엔도뉴클레아제가 Msp I, Hpa Ⅱ, BssH Ⅱ 및 Not I으로 구성된 군에서 선택The method of claim 24, wherein said restriction endonuclease is selected from the group consisting of Msp I, Hpa II, BssH II and Not I 되는 방법.How to be. 제10항에 있어서, 상기 세포 증식성 질환이 뇌, 결장, 비뇨생식기, 폐, 신장, 조혈, 가슴, 흉선, 고환, 난소 및 자궁으로 구성된 군에서 선택되는 조직과 관련된 방법.The method of claim 10, wherein said cell proliferative disease is associated with tissue selected from the group consisting of brain, colon, genitourinary system, lung, kidney, hematopoietic, chest, thymus, testis, ovary and uterus. 제26항에 있어서, 상기 질환이 저급 신경교 성상세포종, 퇴화성 신경교 성상세포종, 신경교아세포종, 수아세포종, 결장암, 폐암, 신장암, 백혈병, 유방암, 전립선암, 자궁내막암 및 신경아세포종으로 구성된 군에서 선택되는 방법.27. The method according to claim 26, wherein the disease is in the group consisting of lower glial astrocytoma, degenerative glial astrocytoma, glioma, blastoma, colon cancer, lung cancer, kidney cancer, leukemia, breast cancer, prostate cancer, endometrial cancer and neuroblastoma The method chosen. HIC-1과 과련된 세포 증식성 질환을 가진 환자에게 HIC-1의 발현을 조절하는 시약을 치료학적으로 유효한 양으로 투여하는 단계를 포함하는, HIC-1과 관련된 세포 증식성 질환의 치료 방법.A method of treating a cell proliferative disease associated with HIC-1, comprising administering to a patient with a cell proliferative disease associated with HIC-1 a therapeutically effective amount of a reagent that modulates the expression of HIC-1. 제28항에 있어서, 상기 시약이 HIC-1 센스 폴리뉴클레오티드 서열을 포함하는 폴리뉴클레오티드 서열인 방법.The method of claim 28, wherein said reagent is a polynucleotide sequence comprising an HIC-1 sense polynucleotide sequence. 제29항에 있어서, 추가로 포함되는 시약이 HIC-1 폴리뉴클레오티드 서열과 작동적 연결 관계인 프로모터를 암호화하는 폴리뉴클레오티드 서열인 방법.The method of claim 29, wherein the additionally included reagent is a polynucleotide sequence encoding a promoter that is in operative linkage with the HIC-1 polynucleotide sequence. 제29항에 있어서, 상기 폴리뉴클레오티드 서열이 발현 벡터내에 존재하는 방법.The method of claim 29, wherein said polynucleotide sequence is in an expression vector. 제28항에 있어서, 상기 질환이 뇌, 비뇨생식기, 폐, 결장, 신장, 조혈, 가슴, 흉선, 고환, 난소 및 자궁으로 구성된 군에서 선택되는 조지과 관련된 방법.29. The method of claim 28, wherein said disease is selected from the group consisting of brain, urogenital, lung, colon, kidney, hematopoietic, breast, thymus, testes, ovary, and uterus. 제32항에 있어서, 상기 질환이 저급 신경교 성상세포종, 퇴화성 신경교 성상세포종, 신경교아세포종, 수아세포종, 결장암, 폐암, 신장암, 백혈병, 유방암, 전립선암, 자궁내막암 및 신경아세포종으로 구성된 군에서 선택되는 방법.33. The method according to claim 32, wherein said disease is in the group consisting of lower glial astrocytoma, degenerative glial astrocytoma, glioblastoma, medulloblastoma, colon cancer, lung cancer, kidney cancer, leukemia, breast cancer, prostate cancer, endometrial cancer and neuroblastoma The method chosen. 제28항에 있어서, HIC-1 관련 세포 증식성 질환이 HIC-1 뉴클레오티드 서열의 과메틸화와 관련된 방법.The method of claim 28, wherein the HIC-1 related cell proliferative disease is associated with hypermethylation of the HIC-1 nucleotide sequence. HIC-1을 암호화하고 프로모터와 작동적 연결 관계에 있는 뉴클레오티드 서열을 포함하는 발현 벡터를 숙주 환자의 세포 속으로 도입시키는 것을 포함하는 유전자 치료 방법.A method of gene therapy comprising introducing into a cell of a host patient an expression vector that encodes HIC-1 and comprises a nucleotide sequence that is in operative connection with a promoter. 제35항에 있어서, 상기 발현 벡터를 환자의 세포내로 생체외에서 도입시키고, 그 세포를 다시 환자에게 도입시키는 방법.36. The method of claim 35, wherein the expression vector is introduced ex vivo into a cell of the patient and the cell is introduced back to the patient. 제35항에 있어서, 상기 발현 벡터가 RNA 비루스인 방법.36. The method of claim 35, wherein said expression vector is an RNA virus. 제37항에 있어서, RNA 비루스가 레트로비루스인 방법.The method of claim 37, wherein the RNA virus is retrovirus. 제35항에 있어서, 상기 환자가 인간인 방법.36. The method of claim 35, wherein said patient is a human. 제35항에 있어서, 상기 질환이 HIC-1 폴리뉴클레오더드의 과메털화와 관련된 방법.36. The method of claim 35, wherein said disease is associated with hypermetalization of HIC-1 polynucleotides. 메틸화된 HIC-1 핵산의 검출용 프로브를 함유하는 제1용기를 포함하여 하나 이상의 용기를 내부에 밀착수용하도록 구획된 캐리어 수단을 포함하는, HIC-1 핵산의 메틸화와 관련된 세포 증식성 질환의 표시인 표적세포 성분의 검출에 유용한 진단 키트.Indication of cell proliferative diseases associated with methylation of HIC-1 nucleic acid, comprising carrier means partitioned to tightly house one or more containers therein, including a first container containing a probe for detection of methylated HIC-1 nucleic acid A diagnostic kit useful for the detection of phosphorous target cell components. 제41항에 있어서, 상기 표적 세포 성분이 HIC-1 폴리펩티드인 키트.42. The kit of claim 41, wherein said target cell component is an HIC-1 polypeptide. 제42항에 있어서, 상기 프로브가 항체인 키트.The kit of claim 42, wherein said probe is an antibody. 제41항에 있어서, 상기 표적 세포 성분이 핵산 서열인 키트.42. The kit of claim 41, wherein said target cell component is a nucleic acid sequence. 제44항에 있어서, 상기 프로브가 폴리뉴클레오티드 혼성화 프로브인 키트.45. The kit of claim 44, wherein said probe is a polynucleotide hybridization probe. 핵산 샘플에서 비정상적인 핵산 메틸화를 검출하는 단계 및 유전자를 동정하는 단계를 포함하는 종양억제 유전자를 동정하는 방법.A method of identifying a tumor suppressor gene comprising detecting abnormal nucleic acid methylation in a nucleic acid sample and identifying a gene. 제46항에 있어서, 상기 핵산이 하나 이상의 CpG 섬 뉴클레오티드 서열을 포함하는 방법.47. The method of claim 46, wherein said nucleic acid comprises one or more CpG island nucleotide sequences. 제47항에 있어서, 상기 CpG 뉴클레오티드 서열이 과메틸화된 것인 방법.48. The method of claim 47, wherein said CpG nucleotide sequence is hypermethylated. ※ 참고사항 : 최초출원 내용에 의하여 공개되는 것임.※ Note: This is to be disclosed by the original application.
KR1019970703250A 1994-11-15 1995-11-15 New tumor suppressor gene HIC-1 (NOVEL TUMOR SUPPRESSOR GENE.HIC-1) KR970706849A (en)

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